OP0106 SOLUBLE PD-1 PROMOTES LOCAL IL-17A PRODUCTION IN THE INFLAMED MICROENVIRONMENT IN SpA
Authors: E. Rasmussen, R. Østgård, M. Hvid, U. Syrbe, D. Poddubnyy, B. Deleuran, S. R. Greisen
Journal: Annals of the Rheumatic Diseases (2022)

Background Programmed death 1 (PD-1) is an immune checkpoint receptor expressed by activated T-cells. Activation of the PD-1 pathway reduces T cell activation and inflammation. Targeting PD-1 in cancer can result in autoimmune disease, which highlights the importance of this pathway in balancing inflammation. Both PD-1 and its ligands are present in soluble (s) forms, and we have previously showed that sPD-1 is associated to bone erosions in rheumatoid arthritis. Spondyloarthritis (SpA) is characterized by both bone erosions and bone formation. Current evidence suggests an important interaction between the PD-1 pathway and the proinflammatory cytokine IL-17A. IL-17A is central in promoting inflammation in SpA and direct osteoclast activation leading to bone erosion. We have previously demonstrated that the PD-1 ligand, PD-L2, reduces osteoclast formation under inflammatory conditions. Objectives We aimed at investigating the interplay between the PD-1 pathway and IL-17A in relation to inflammation and bone homeostasis in patients with SpA. Methods From early SpA patients, plasma was collected at baseline and after 1 year of treatment with Adalimumab. From chronic SpA patients, plasma, synovial fluid (SF), peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected. Plasma and PBMCs were also collected from healthy controls (HC) for comparison. Disease activity was measured by ASDAS and progression by inflammation and new bone formation in the total spine. Facet joint biopsies were collected from SpA patients during surgery for correction of rigid hyperkyphosis. Levels of sPD-1 and sPD-L2 were measured in plasma and SF. Surface expression of PD-1 and CCR6 was evaluated on PBMCs and SFMCs. Levels of IL-17A were measured in the supernatant from stimulated PBMC cultures with recombinant human (rh)PD-1. Facet joint biopsies were stained for the presence of PD-1, PD-L1, PD-L2 and CCR6. Results Plasma levels of sPD-1 and sPD-L2 were equally increased in both early and chronic SpA compared to HC. Plasma levels of sPD-1 and sPD-L2 did not change following one year of treatment. In chronic SpA patients, sPD-1 levels were higher in SF than in plasma. Levels of sPD-1 and sPD-L2 in plasma and SF did not correlate with any disease activity scores or progression. Expression of PD-1 on the cell surface of PBMCs from SpA patient was comparable to healthy controls. On SFMCs, PD-1 expression was increased, supporting continuous T-cell activation in the local microenvironment. After stimulation with anti CD3/CD28, SpA PBMCs produced more IL-17A when cultured with rhPD-1 compared to healthy control PBMCs. PD-1 and CCR6 were highly present in facet joint biopsies, but PD-L2 and PD-L1 could not be detected. This supports the PD-1 pathway to play a role at the actual site of pathology. Conclusion Plasma levels of the PD-1 family is unaffected by addition of anti-TNFα antibody treatment in SpA. The early SpA cohort had a low degree of progression in structural changes in the observation period, which could explain the lack correlation with sPD-1 and sPD-L2 and disease progression. Soluble PD-1 is high in the inflamed microenvironment, where it may result in increased IL-17A production. Collectively, these data suggest that the PD-1 pathway could play a role in the pathogenesis of SpA, acting in the inflamed microenvironment. Disclosure of Interests None declared